Acquired brain damage arises both from the primary insult and delayed, secondary cell death in sub-cortical structures such as the thalamus. Our research and that of others have demonstrated that delayed apoptotic cell death in the immature thalamus occurs much more rapidly than in the adult thalamus. Understanding the increased vulnerability of the immature brain is therefore essential for the development of targeted therapies. Thus, this research-training program seeks to define the molecular basis for age-dependent responses to secondary brain injury, leading to effective therapies for the brain-injured child. A validated and reliable in vivo murine model of occipital cortical ablation leading to thalamocortical neuronal death will be used to determine these age-dependent responses. Given the importance of such research and the availability of this murine model, a 5-year, multidisciplinary research and training program that focuses on thalamocortical neuronal death following target deprivation neurotropin withdrawal injury is proposed. Based on compelling preliminary data obtained from analyses of 12,000 element microarrays that identified both induction of pro-apoptotic genes and repression of genes encoding antioxidants such as metallothionein I and II, the research will address three hypotheses. 1) Neuronal maturity will influence the sequence of coordinately regulated gene expression leading to target deprivation-induced neuronal apoptosis. Using both stereologic and gene expression techniques, in vivo progression of delayed, secondary neuronal injury in mouse pups and adults will be compared. 2) Neurotrophin administration rescues thalamocortical projection neurons from apoptotic cell death. Using similar techniques, the response to brain derived neurotropic factor versus placebo administration will be compared. 3) Modifying compensatory response to oxidative stress in the immature brain to resemble those found in the mature brain will slow the rate of target-deprivation-induced cell death. The effects on cell death, oxidant injury, and gene expression will be compared in transgenic mice with augmented metallothionein I expression. This research grant extends the investigator's capabilities through mentorship and training in specific techniques (e.g. laser capture microdissection). In addition, it will provide sophisticated skills in the analysis and interpretation of data required to address complex pathophysiological processes from the genetic to the cellular level. Mentors in molecular genetics and neuroscience as well as the resources of the Mental Retardation and Developmental Disabilities Research Center will support well-defined training objectives.